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1 Mutations in PIK3C2A Cause Syndromic Short Stature, Skeletal bioRxiv preprint doi: https://doi.org/10.1101/488411; this version posted December 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction Dov Tiosano,1,2,17 Hagit Baris Feldman,2,3,17 Anlu Chen,4,17 Marrit M. Hitzert,5,17 Markus Schueler,6,17 Federico Gulluni,7,17 Antje Wiesener,8 Antonio Bergua,9 Adi Mory,3 Brett Copeland,10 Joseph G. Gleeson,10,11 Patrick Rump,5 Hester van Meer,12 Deborah A. Sival,12 Volker Haucke,13 Josh Kriwinsky14, Karl X. Knaup,6 André Reis,8 Nadine N. Hauer,8 Emilio Hirsch,7 Ronald Roepman,15 Rolph Pfundt,15 Christian T. Thiel,8,18 Michael S. Wiesener,6,18 Mariam G. Aslanyan,15,18 and David A. Buchner4,14,16,18* 1Division of Pediatric Endocrinology, Ruth Children's Hospital, Rambam Medical Center, Haifa 30196, Israel. 2Rappaport Family Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 30196, Israel. 3The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel. 4Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA. 5Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001 9700 RB Groningen, The Netherlands. 6Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen- Nürnberg, Erlangen, Germany. 7Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126, Torino, Italy. 8Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. 9Department of Ophthalmology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. 10Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA. 11Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA. 12Department of Pediatrics, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, PO Box 3001 9700 RB Groningen, the Netherlands. 13Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin Faculty of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany. 1 bioRxiv preprint doi: https://doi.org/10.1101/488411; this version posted December 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 14Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. 15Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 16Research Institute for Children’s Health, Case Western Reserve University, Cleveland, OH 44106, USA. 17These authors contributed equally to this work 18These authors contributed equally to this work * [email protected] 2 bioRxiv preprint doi: https://doi.org/10.1101/488411; this version posted December 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease. 3 bioRxiv preprint doi: https://doi.org/10.1101/488411; this version posted December 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Introduction Identifying the genetic basis of diseases with Mendelian inheritance provides insight into gene function, susceptibility to disease, and can guide the development of new therapeutics. To date, ~50% of the genes underlying Mendelian phenotypes have yet to be discovered (Chong et al., 2015). The disease genes that have been identified thus far have led to a better understanding of the pathophysiological pathways and to the development of medicinal products approved for the clinical treatment of such rare disorders (Boycott et al., 2013). Furthermore, technological advances in DNA sequencing have facilitated the identification of novel genetic mutations that result in rare Mendelian disorders (Koboldt et al., 2013; Sobreira et al., 2015). We have applied these next-generation sequencing technologies to discover mutations in PIK3C2A that cause a newly identified genetic syndrome consisting of dysmorphic features, short stature, cataracts and skeletal abnormalities. PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases that catalyzes the phosphorylation of phosphatidylinositol (PI) (Cantley, 2002). The functions of class II PI3Ks are poorly understood. However, they are generally thought to catalyze the phosphorylation of PI and/or PI 4-phosphate [PI(4)P] to generate PI(3)P and PI(3,4)P2, respectively (Jean and Kiger, 2014). PIK3C2A has been attributed a wide-range of biological functions including glucose transport, angiogenesis, Akt activation, endosomal trafficking, phagosome maturation, mitotic spindle organization, exocytosis, and autophagy (Behrends et al., 2010; Campa et al., 2015; Devereaux et al., 2013; Falasca and Maffucci, 2012; Franco et al., 2014; Gulluni et al., 2017; Krag et al., 2010; Leibiger et al., 2010; Posor et al., 2013; Yoshioka et al., 2012). In addition, PIK3C2A is critical for the formation and function of primary cilia (Falasca 4 bioRxiv preprint doi: https://doi.org/10.1101/488411; this version posted December 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. and Maffucci, 2012; Franco et al., 2014). However, there is as yet no causal link between PIK3C2A, or any class II PI3K, and human disease. Here, we describe the evidence that homozygous loss-of-function mutations in PIK3C2A cause a novel syndromic disorder involving neurological, visual, skeletal, growth, and occasionally hearing impairments. Results Five individuals between the ages of 8 and 21 from three unrelated consanguineous families were found by diagnostic analyses to have a similar constellation of clinical features including dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts (Figure 1, Table 1, Table S1). The dysmorphic facial features included coarse facies, low hairline, epicanthal folds, flat and broad nasal bridges, and retrognathia (Figure 1B, Table S1). Skeletal findings included scoliosis, delayed bone age, diminished ossification of femoral heads, cervical lordosis, shortened fifth digits with mild metaphyseal dysplasia and clinodactyly, as well as dental findings such as broad maxilla incisors, narrow mandible teeth, and enamel defects (Figures 1C, 1D, Table S1, Figure S1). Most of the affected individuals exhibited neurological involvement including developmental delay and stroke. This was first seen in individual I-II-2 when she recently started having seizures, with an EEG demonstrating sharp waves in the central areas of the right hemisphere and short sporadic generalized epileptic seizures. Her brain MRI showed a previous stroke in the right corpus striatum (Figure 1F). Hematological studies were normal for hypercoagulability and platelet function (Table S2). In addition, brain MRI of patient II-II-3 showed multiple small frontal and periventricular lacunar infarcts (Figure S1E). Unclear episodes of syncope also led to neurological investigations including EEG in individual III-II-2, without any signs of epilepsy. Her brain MRI showed symmetrical structures and normal cerebrospinal 5 bioRxiv preprint doi: https://doi.org/10.1101/488411; this version posted December 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. fluid spaces but pronounced
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